Process for the preparation of a methylketone related to estrone



United States Patent PROCESS FOR THE PREPARATION OF A METHYL- KETONERELATED TO ESTRONE Leon Velluz and Georges Muller, Paris, France,assignors t0 Les Laboratoires Francais de Chimiotherapie, Paris, France,a body corporate No Drawing. Application February 20, 1952, Serial No.272,706

Claims priority, application France January 2, 1948 5 Claims. (Cl.260-3974) wherein R is a methyl group and X a member of a group selectedfrom the groups, consisting of a hydroxyl group and a group convertible,by hydrolysis, into a hydroxyl group, such as an ester group.

These novel methyl ketone compounds, in addition to their utility in thesynthesis of useful related substances, are physiologically active andmay be employed in human or veterinary medicine as estrogenic substancesand also in the treatment of certain types of malignant tumors, such asprostatic carcinoma.

In general terms, the synthesis of these novel compounds is effected asfollows: estrone is treated with an acylating agent to convert the3-hydroxy group to an acyloxy group; the reaction product is thenreacted with hydrogen cyanide whereby the 17-keto group is converted toa cyanohydrin group; this compound is then treated with a dehydratingagent to split off water between the carbon atoms 16 and 17 and toproduce the corresponding nitrile with an unsaturated linkage betweencarbon atoms 16 and 17 of the ring system and a nitrile substituent in17-position. This last mentioned reaction product, after being reactedwith Grignard reagent followed by conversion to the correspondingketimine and hydrolysis, yields the corresponding 17-methyl ketonecompound, unsaturated in the linkage between the carbon atoms in 16- and17-positions of the ring system and with a -COCH3 substituent in17-position. Said unsaturated methyl ketone compound is thenhydrogenated to cause addition of hydrogen solely to the A16,17-doublebond of the ring system, yielding the desired saturated methyl ketonecompound of the formula set forth above. Derivatives of the 3-hydroxygroup of said methyl ketone, such as the acyloxy derivatives, areobtained in the course of the.

above described reaction by subsequent acylation of the 3- ydroxy groupin the Al6,l7-unsaturated as well as in the saturated final l7-methylketone.

The synthesis may be represented by the following formulas, X beingacyloxy and Hal being a halogen:

o H: C H: 0 0

acylatlng agent I II ' HCN 0 H3 0 N p j dehydrating agent X IV MethylGrignard \hydrogenating compound agent C H: v C H:

O-GH: 0N

NMgHal \hydrollzing agent (I? O C Ha VI hydrogenating/ \acylating agentr/ agent 0 H3 CH;

C O C Ha (I O C H:

HO X- VII VIII acyla ti1\ yd at to en in agent \i agen t g As acylatingagents there are preferably used acid anhydrides and acid halogenides.One may, however, employ the acids themselves, especially in thepresence of catalysts p le of acc l rating pl t n fi. f ater. Espciallysuitable, acylating agents are acetic acid anhydride or acetylchloride, preferably in the presence of a tertiary base, such aspyridine, diethyl aniline, quinoline and the like, and, in the case ofthe acid chloride, of an alkaline agent, such as, sodium hydroxide,carbonate, bicarbonate and the like. It is also possible, first to.produce a salt, preferably an alkali salt of the phenolic hydroxyl groupin estrone, and then to react said salt with an acid halogenide. One mayfurthermore proceed by reacting the phenolic compound and thecorresponding acid or its alkali salt in the presence of phosphorusoxychloride, phosphorus pentachloride and the like. Other methods ofacylating said phenolic starting materials, such as estrone or theunsaturated or saturated methyl ketones obtained according to thisinvention, as they are known in the art, may also be used. In the placeof acetic acid and its anhydride or chloride, other aliphatic as well asaromatic and heterocyclic acids and their anhydrides and halogenides maybe reacted, such as propionic acid, butyric acid, valeric acid, stearicacid, palmitic acid, oleic acid, oxalic acid, malonic acid, adipic acid,acrylic acid, maleic acid, fumaric acid, or substituted aliphatic acids,such as chloro acetic acid, lactic acid, tartaric acid, malic acid,citric acid and others. Cycloaliphatic acids and their anhydrides andhalogenides, such as saturated and unsaturated cyclopentane carboxylicacids, cyclohexane carboxylic acids and the like may also be used. Themost suitable aromatic carboxylic acid or its reactive derivative whichmay be reacted according to this invention, is benzoyl chloride, butother aromatic acids and their halogenides or anhydrides, such assubstituted benzoic acids like p-nitrobenzoyl chloride, m-nitro benzoylchloride, the halogenides of methyl benzoic acids, phenyl acetic acid,cinnamic acid, hydrocinnamic acid, phthalic acid, salicylic acid,anthranilic acid, hippuric acid, mandelic acid and others may also beemployed. Suitable heterocyclic acids are, for instance, nicotinic acidand other pyridine carboxylic acids, furane-Z-carboxylic acid, quinolinecarboxylic acids and others.

To produce the cyanohydrin compound, hydrocyanic acid as such is addedto the ketonic starting material. Said hydrocyanic acid may also beproduced in statu nascendi, for instance, by using a mixture of analkali cyanide and an organic acid, such as potassium cyanide and aceticacid.

The dehydration of the cyanohydrin compound to the corresponding nitrilecompound is carried out in a manner known per se by means of agentscapable of splitting off water. Phosphorus halogenides, such asphosphorus oxychloride, preferably in a solvent capable of bindinghalogen hydride, such as a tertiary base like pyridine, has proved to beespecially suitable.

As Grignard reagent, the magnesium compounds of methyl halogenides, suchas methyl magnesium bromide are preferably used. It is, of course,possible to react the nitrile with other suitable organo-metalliccompounds, such as zinc methyl, lithium methyl and the like.

Hydrolysis of the Grignard reaction product of the nitrile is effected,for instance, by heating with inorganic or organic acids, such asalcoholic sulfuric acid, aqueous ammonium chloride solution, glacialacetic acid, dilute aqueous acetic acid and others.

The Al6,17-double bond in the unsaturated ketone obtained thereby ishydrogenated by any known means capable of adding hydrogen to and,thereby, saturating a double bond. In particular, it is recommended toemploy catalytically activated hydrogen. As catalysts there are usedsuch catalysts which do not cause hydrogenation of aromatic compounds,i. e. catalysts of comparatively mild activity, especially activatednickel catalysts and preferably Raney nickel which is employed atordinary pressure and room temperature in neutral or weakly alkalinemedium.

It is, of course, also possible to first hydrogenate the unsaturatednitrile to the corresponding saturated nitrile, to react said nitrilewith a methyl Grignard compound, to hydrolyze the ketimine obtainedthereby and, if required, to acylate the saturated methyl ketone.

In the course of this reaction new and valuable intermediate and finalproducts are obtained, namely the cyanohydrin of Formula III and its3-acyloxy derivatives,

the unsaturated nitrile of Formula IV and its 3-acyloxy derivatives, andthe saturated and unsaturated l7-methyl ketones of Formulas VII and VIand their 3-acyloxy derivatives.

The following examples describe in detail the synthesis of theintermediate and final products according to this invention as mentionedabove.

EXAMPLE 1 3-acet0xy-17-ket0-A-1,3,5-estratriene (estrone acetate) 3 g.of estrone (I) are dissolved in 20 cc. of pyridine and 15 cc. of aceticacid anhydride are added to said solution. The mixture is heated underreflux at C. on an oil bath for an hour and a half. The reaction mixture is cooled, 200 cc. of water and thereafter 10 cc. of methanol areadded, and the solution is extracted with ethyl acetate. The extract isacidified to a pH of 3.0 by the addition of dilute sulfuric acid (1:5).The-estrone acetate solution is Washed wih Water, dried, and distilledto dryness. The residue is recrystallized from eth-v anol. The pureestrone acetate (II) obtained thereby has a melting point of 12317124 C.

3-acet0xy-1 7-cyanohydrin-4I ,3 ,5 estz'a tri ene (Ill 3 -acet0xy-17-cyano-A-1 ,3,5 ,1 6-estratetraene (IV) 1 g. of the cyanohydrin (III)obtained as described above, 3 cc. of anhydrous pyridine and 1 cc. ofphosphorus oxychloride are placed into a heavy-walled glass tube. Thetube is sealed and heated for an hour and a half at a temperature of 150C. in an oil bath. After cooling to about C. the tube is opened and theliquid poured on ice. The mixture is acidified to a pH of 3.0 by theaddition of hydrochloric acid, and the reaction product is extracted bymeans of ethyl acetate. The extract is washed with water, dried anddistilled to dryness. The residue is recrystallized from ethanol. Thenitrile (IV) obtained has a melting point of 114-7115 C. (oc) =|72;(CHCla, C=0.5%).

3-hydroxy-17-methylket0-A-1,3,5,1fiagtsratezraene (VI) Into a flaskprovided with a reflux cooler, there are introduced 3 g. of magnesiumand 40 cc. of ether. Thereto sufficient (15 to 20 g.) liquid methylbromide is added in small amounts until the magnesium is completelydissolved. l g. of the nitrile (IV) obtained as described above, isadded to said solution and the mixture is heated under reflux at atemperature between 50 and 60 C. for a period of 24 hours. The reactionmixture is poured on ice and the resulting magnesium compound isdissolved in 20 cc. ofglacial acetic acid. After heating the reactionmixture at 100 C. for one hour, the precipitated ketimine is filteredoff, dissolved in 20 parts by volume of glacial acetic acid; then 2parts by volume of water are added, and heated under reflux at 100 C.for 15 minutes. Hydrolysis of the ketimine produces the unsaturatedmethylketone (VI) which contains no acetoxy group in 3-position, but afree hydroxy group and has a melting point of 256 C. (PC)D=+1IS;(CI-ICls, C=0.2%

3-hydr0xy-17-methylket0-AI,3,5-estratriene (VII) 1 g. of the unsaturatedketone (VI) obtained as described above is dissolved in cc. of ethanol.1 g. of Raney nickel catalyst is added to said solution and the pH ofthe same is adjusted to about 10.0 by the addition f a few dr p of a soium h d xid sciat a.- H drogen is then passed through the mixture untilthe saturated methylketone v i p D cipitated from the reaction mixtureby the addition of water. It is filtered off and recrystallized fromethanol.

Its melting point is 254 C. (a) =+151; (CHCls, C: 0.5%

The 3-hydroxy-17-methyl keto-A1,3,5-estratriene obtained hereby isphysiologically active and is employed therapeutically as mentionedabove.

It is converted into its esters as described 1n the following examples.

EXAMPLE 2 80 mg. of 3-hydroxy-17-methyl keto-A1,3,5-estratriene EXAMPLE3 150 mg. of 3-hydroxy-l7-methyl ketoAl,3,5-estratriene (VII) aredissolved in 5 cc. of benzene. 0.5 cc. of pyridine and 0.5 cc. ofbenzoyl chloride are added thereto and the mixture is heated at 70 C.for about minutes. The reaction mixture is worked up as described above,and yields, after recrystallization from ethanol, the benzoate of3-hydroxy-l7-methyl keto-A1,3,5-estratriene (IX), having a melting pointof 170l72 C. (00 +110 C. +2 (in chloroform). Yield: about 80%.

In a similar manner, other esters of said 3-hydroxy-. 17-methylketo-Al,3,5-estratriene (VII) are obtained, for instance, with propionylchloride the propionate, with stearic acid chloride the stearate, andwith other acids and their anhydrides or halogenides other esters ofsaid 5 methyl ketone, as heretofore set forth.

Likewise, when starting with other esters of estrone, such as thepropionate, the valerate, the stearate, the benzoate, the nicotinate andthe like, other 3-esters of the cyanohydrin of Formula III or of theunsaturated and saturated nitriles of Formulas IV and X respectively areobtained. On saponifying said esters the corresponding 3-hydroxycyanohydrins or unsaturated or saturated nitriles are produced.

The unsaturated 3-hydroxy-l7-methyl keto-A-1,3,5,16- estratetraene (VI)may also be converted into its acyloxy derivatives in a similar manneras described above whereby 3-acyloxy-l7-methylketo-A1,3,5,l6-estratetraene compounds of Formula VIII are formed,which, in turn, may

be hydrogenated to the saturated 3-acyloxy-17-methylketo-Al,3,5-estratriene compounds of Formula IX.

Of course, many other changes and variations in the reaction compounds,the reaction conditions, the solvents used, the reaction temperature andduration, the methods of working up the reaction mixure and of isolatingand purifying the reaction product and the like may be made by thoseskilled in the art in accordance with the principles set forth hereinand in the claims annexed hereto.

We claim: 1. As a new product, a steroid compound selected from thegroup consisting of 3-hydroxy-l7-methyl keto- A1,3,5-estratriene,3-acetoxy-17-methyl keto-A1,3,5-estratriene, 3-benzoyloxy-l7-methylketo-Al,3,5-estratriene, and 3-hydroxy-17-methylketo-Al,3,5,l6-estratetraene.

2. As a new product, 3-acetoxy-l7-methyl keto-A1,3,5- estratriene of thefollowing formula C 0-CH;

CH3.C 0.0

3. As a new product, 3-benzoyloxy-l7-methyl keto 0 Al,3,5-estratriene ofthe following formula C OCH;

4. As a new product, 3-hydroxy-17-methyl keto-A1,3,5- estratriene of thefollowing formula C 0CH:

5. As a new product, 3-hydroxy-l7-methyl keto- A1,3,5,16-estratetraeneof the following formula No references cited.

1. AS A NEW PRODUCT, A STEROID COMPOUND SELECTED FROM THE GROUPCONSISTING OF 3-HYDROXY-17-METHYL KETO$1,3,5-ESTRATRIENE,3-ACETOXY-17-METHYL KETO-$1,2,3-ESTRATRIENE, 3-BENZOYLOXY-17-METHYLKETO-$1,3,5-ESTRATRIENE, AND3-HYDROXY-17-METHYL-KETO-$,1,3,5,16-ESTRATETRAENE.